Mitochondrial permeability transition pore (mPTP) opening plays a critical role in cardiac
reperfusion injury and its prevention is cardioprotective. Tumour cell mitochondria usually have high levels of
hexokinase isoform 2 (HK2) bound to their outer mitochondrial membranes (OMM) and HK2 binding to heart mitochondria has also been implicated in resistance to
reperfusion injury. HK2 dissociates from heart mitochondria during ischaemia, and the extent of this correlates with the
infarct size on reperfusion. Here we review the mechanisms and regulations of HK2 binding to mitochondria and how this inhibits
mPTP opening and consequent
reperfusion injury. Major determinants of HK2 dissociation are the elevated
glucose-6-phosphate concentrations and decreased pH in ischaemia. These are modulated by the myriad of signalling pathways implicated in preconditioning protocols as a result of a decrease in pre-ischaemic
glycogen content. Loss of mitochondrial HK2 during ischaemia is associated with permeabilization of the OMM to
cytochrome c, which leads to greater
reactive oxygen species production and
mPTP opening during reperfusion. Potential interactions between HK2 and OMM
proteins associated with mitochondrial fission (e.g. Drp1) and apoptosis (
B-cell lymphoma 2 family members) in these processes are examined. Also considered is the role of HK2 binding in stabilizing contact sites between the OMM and the inner membrane. Breakage of these during ischaemia is proposed to facilitate
cytochrome c loss during ischaemia while increasing
mPTP opening and compromising cellular bioenergetics during reperfusion. We end by highlighting the many unanswered questions and discussing the potential of modulating mitochondrial HK2 binding as a pharmacological target.